‘A crack in the door’: Glimpses of hope for the future of brain cancer care

Fred Hutch researchers discuss brain tumor treatments in the works — and what’s coming next
Dr. Eric Holland
Neurosurgeon and brain cancer researcher Dr. Eric Holland is among the researchers at Fred Hutch pursuing new and better treatments for patients with brain tumors. Photo by Matt Hagen for Fred Hutch

When Vice President Joe Biden visited Fred Hutchinson Cancer Research Center Monday, he spoke of the hundreds of thousands of people who die from cancer every year, and the millions of lives that could be saved with new approaches to treatment, access to care, prevention, and cures.

But for Biden, one person inspired his commitment to the cancer moonshot: his oldest son, Joseph “Beau” Biden, who died last year of brain cancer at the age of 46.

Biden said Monday he’ll stick with the job of eliminating cancer for the rest of his life. He’s focused on the lives affected by all types of cancer, but mentioned his son’s disease and death several times in the panel discussion that included researchers from Fred Hutch and other Seattle-area institutions.

"When you have someone you love who is essentially given a death sentence, you try to learn everything you possibly can [to see] if there is any alternative, any option, anything you can possibly do," Biden said during the discussion.

There are more than 120 different types of brain tumors, afflicting nearly 700,000 people in the U.S. and killing nearly 17,000 every year, according to the American Brain Tumor Association. The Biden family didn’t disclose Beau’s type of brain cancer, but some have speculated it was likely a glioblastoma, a particularly aggressive type of brain tumor that is among the most common adult brain cancers.

Glioblastoma is universally fatal, said Fred Hutch neurosurgeon Dr. Eric Holland, whose brain cancer research team focuses on this tumor type. Patients with the more aggressive form of this cancer have a median survival of about 15 months following diagnosis, even with the standard-of-care treatment.

Right now, the standard treatment for glioblastoma is a combination of surgery, radiation, and chemotherapy. There are few options when those fail, but Holland is cautiously optimistic for the future. He believes with an as-yet-to-be-determined combination of immunotherapy and precision medicine, brain cancer researchers may finally make some headway against this long intractable problem.

“For a long time this has been a very hopeless field. A lot of people who were in it were either idealists who were imagining somehow changing the world — or nihilists who knew they couldn’t. It’s been a very hard problem,” said Holland, who puts himself in the idealist camp. “But all that said, I think there actually is a crack in the door right now.”

Early days and unique challenges

Holland is quick to point out that nobody has yet shown that immunotherapy can hold a candle against glioblastoma. T-cell therapy, a treatment in which a patient’s own immune cells are engineered to recognize and attack their tumors and which is showing promise for certain blood cancer patients, is being used in some small, early-stage clinical trials in glioblastoma at some other research centers. But, even for blood cancers, it’s still early days for this experimental therapy.

Brain cancer, especially glioblastoma, poses a series of unique challenges to treatment, Holland said. Some solid tumors arise in organs that can be removed or transplanted, if the cancer is caught early enough. But obviously that doesn’t apply to the brain — “that’s who you are,” Holland said.

The blood-brain barrier, which keeps the brain and its associated fluid tightly isolated from the circulatory system, also poses a challenge — many drugs simply can’t access tumors. Glioblastoma is resistant even to those drugs that can get in and it’s also more resistant to radiation than even normal brain tissue is.

Finally, unlike some other brain tumors, glioblastoma is very difficult to completely remove surgically because it’s so diffuse in the brain.

“The tumor cells are like a puff of smoke in the room, or ants in the grass. They’re just everywhere,” Holland said.

Holland is hopeful, though, that his particular area of expertise — precision oncology — can lay the groundwork for better treatments for glioblastoma, as it may for any cancer. He’s leading the development of Hutch Integrated Data Repository and Archive, or HIDRA, a database to combine patients’ clinical information with the genetic information of their individual tumors. The ultimate goal of databanks like HIDRA and the data visualization tool Oncoscape is to better understand how a patient is likely to respond to a given treatment and to tailor their care accordingly, Holland said.

“It’s like a much more granular diagnosis,” he said.

Unfortunately, even if researchers better understood the molecular details of patients’ tumors, there are few treatment options. But one day there will be more alternatives, Holland said, and when that day comes, he believes the framework of precision medicine will help guide the testing and tailoring of those new treatments — be they immunotherapies or new drugs.

Dr. Jim Olson
Pediatric brain cancer researcher Dr. Jim Olson is investigating ways to improve brain cancer surgery and treatment. Photo by Robert Hood / Fred Hutch News Service

‘Following the light’ to better brain cancer treatments

Fred Hutch pediatric brain cancer researcher Dr. Jim Olson has been plugging away at a better way to surgically remove brain tumors since 2004, when he led a team that invented the molecule now known as Tumor Paint BLZ-100. This invention, now being tested in five different early-phase clinical trials for cancers including brain cancer, with more than 60 adult and pediatric patients enrolled, “lights up” brain tumors with a fluorescent dye that attaches only to cancerous cells.

Pinpointing what is tumor and what is not could potentially allow brain surgeons to more precisely remove the tumor and leave healthy tissue behind. Removing healthy parts of the brain along with the tumor can leave patients with lasting disabilities, Olson said, but leaving parts of the tumor behind is also dangerous because it can regrow.

“Getting it right is particularly important for brain tumors, because in both kids and adults the likelihood of survival is dramatically higher if most of the tumor is removed,” he said.

The early-stage clinical trials are conducted by Blaze Bioscience Inc., a company Olson founded in 2010, and the trials are testing the safety of the tumor paint molecule in different doses. So far, Olson said, he and his team haven’t seen any significant toxicity and the drug seems to be lighting up tumors in many of the patients enrolled in the trial, although it’s too early to say whether the treatment improves’ patients survival.

Brain tumors make up a higher proportion of solid tumors in children than in adults. There are more than 30 types of pediatric brain tumors, Olson said.

Nina Garkavi
Nina Garkavi was diagnosed with a pediatric brain tumor in 2011 at the age of 22. Photo courtesy of Nina Garkavi

Nina Garkavi, who was diagnosed with the pediatric brain tumor medulloblastoma in 2011, said she feels lucky to have come through her treatment alive and (relatively) unscathed, but wonders whether her life would be different now had something like tumor paint been available when she had her two brain surgeries five years ago.

“Would it be different if I had some treatment like that and a surgical version with tumor paint? Would I have the same effects?” asked Garkavi, who had to completely relearn how to walk after her surgeries. The now-27-year-old Seattle University graduate student used to be right-handed but had to teach herself how to write with her left hand, she said, as she had tremors on her right side and her right hand even now sometimes “has a mind of its own.”

Building on the back of Tumor Paint BLZ-100, Olson and his team are also working to develop similar molecules that target existing chemotherapies directly to tumors, sparing healthy tissue from chemo’s normally toxic side effects.

“One of the most common questions I’m asked when I talk about tumor paint is, if you can deliver light to the cancer, why can’t you deliver drugs to the cancer?” Olson said.

Those therapies are still in preclinical studies, but Olson said that since these molecules are much smaller than many other brain cancer drugs, they have the potential to successfully cross the blood-brain barrier and reach the brain tumors.

“We believe that if we ‘follow the light’ by treating patients whose tumors light up with tumor paint with a subsequent molecule that delivers chemotherapy to the remaining cells in their body, that would have potential to effectively treat the cancer while causing fewer side effects,” he said.

Dr. Hans-Peter Kiem
Dr. Hans-Peter Kiem is testing a gene therapy approach to protect glioblastoma patients' blood cells from toxic side effects of treatment. Photo by Matt Hagen for Fred Hutch

Protecting blood cells from toxic effects

Fred Hutch gene therapy experts Drs. Hans-Peter Kiem and Jen Adair are leading a small, early-stage clinical trial that takes a different tack against glioblastoma — using gene editing to protect blood stem cells from a drug that can boost chemotherapy’s effectiveness against the cancer. Some patients with glioblastoma produce a certain protein in their tumors that make the cancer uniquely resistant to chemotherapy. There is a drug that “can unlock the tumor cell to that chemotherapy,” Kiem said in a recent interview, but that drug molecule is very harmful to blood cells.

Kiem and his research colleagues developed a strategy to protect the blood cells from those side effects by engineering the cells in the lab with a gene that shields them from the molecule, known as benzylguanine, and then transplanting the cells back into the patient before proceeding with chemotherapy cycles. Because the patients can now receive benzylguanine safely, they can be treated with lower doses of chemotherapy than the standard treatment dose, meaning the treatment is less toxic overall while still attacking the cancer.

The gene-editing treatment is not a cure, but it is showing promise to give these high-risk patients more precious time. They’ve now treated 10 patients with glioblastoma in the trial, and “eight are now out far enough that we can say all of these patients have survived longer than the [median survival of] 15 months,” Kiem said.

Though new treatments for brain cancer are still highly experimental, they are offering hope for the future, Holland said.

“I think there’s a real chance that in many cancers — and brain cancer may be one of them — we can improve what we do for people,” he said.

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Solid tumors, such as those of the brain, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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